{"gene":"SNX10","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2011,"finding":"SNX10 interacts with the V-ATPase complex and targets it to the centrosome where ciliogenesis is initiated; SNX10 and V-ATPase together regulate ciliary trafficking of Rab8a, a critical regulator of ciliary membrane extension, establishing an SNX10/V-ATPase vesicular trafficking pathway required for ciliogenesis in vitro and in zebrafish in vivo.","method":"Loss-of-function assay in cultured cells and zebrafish morpholino knockdown; co-immunoprecipitation; confocal imaging of centrosomal targeting; rescue experiments","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction data, in vitro and in vivo (zebrafish) loss-of-function with specific phenotypic readout, pathway placement via epistasis with V-ATPase and Rab8a","pmids":["21844891"],"is_preprint":false},{"year":2012,"finding":"SNX10 is required for RANKL-induced osteoclast formation and resorption activity; silencing SNX10 inhibits osteoclast differentiation, bone resorption on hydroxyapatite, and TRAP secretion. SNX10 localizes to the nucleus and endoplasmic reticulum in osteoclasts.","method":"siRNA knockdown of SNX10 in RANKL-stimulated osteoclast precursors; confocal immunofluorescence; subcellular fractionation; qPCR; hydroxyapatite resorption assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotypes using multiple orthogonal assays, single lab","pmids":["22174188"],"is_preprint":false},{"year":2012,"finding":"A missense mutation in SNX10 in osteopetrosis patients results in an abnormally abundant mutant protein with altered distribution, fewer and smaller osteoclasts with markedly deranged resorptive capacity, and a perturbed endosomal pathway as evidenced by altered distribution of internalized dextran.","method":"Homozygosity mapping; analysis of patient osteoclasts; dextran endocytosis assay; immunostaining for SNX10 distribution","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional analysis of patient-derived osteoclasts with endosomal pathway readout, multiple patients studied","pmids":["22499339"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of SNX11 reveals a novel extended PX (PXe) domain with two additional C-terminal α-helices; these helices are indispensable for SNX11 in vitro function and the same PXe domain architecture is proposed to be present in SNX10, responsible for its vacuolation activity.","method":"X-ray crystallography of truncated SNX11; mutagenesis of C-terminal helices; vacuolation functional assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutagenesis validation, but direct structural work was on SNX11 with inference to SNX10","pmids":["23615901"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of human SNX10 at 2.6 Å resolution reveals an extended phox-homology (PXe) domain; Tyr32 and Arg51 are important for protein stability and vacuolation activity; disease-associated mutation Arg16Leu may affect SNX10 function through protein-protein interactions.","method":"X-ray crystallography; structure-guided mutagenesis; vacuolation activity assay","journal":"Proteins","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutagenesis and functional vacuolation assay validating residue-level mechanism in a single rigorous study","pmids":["25212774"],"is_preprint":false},{"year":2015,"finding":"Snx10-deficient osteoclasts show severely defective endocytosis, extracellular acidification, ruffled border formation, and bone resorption. Snx10 is also highly expressed in stomach epithelium and its loss leads to high stomach pH and impaired calcium absorption, causing rickets in addition to osteopetrosis.","method":"Global and osteoclast-specific Snx10 knockout mice; endocytosis assays; extracellular acidification measurement; histology of ruffled borders; bone resorption assays; stomach pH measurement; calcium supplementation rescue experiment","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with multiple orthogonal functional readouts and pharmacological rescue, clearly dissecting two tissue-specific mechanisms","pmids":["25811986"],"is_preprint":false},{"year":2017,"finding":"SNX10 co-localizes with MMP9 and participates in MMP9 trafficking and secretion; SNX10 knockdown reduces MMP9 secretion and activity while increasing intracellular MMP9 protein; SNX10 knockout osteoclasts show downregulated phosphorylation of JNK, p38, and ERK, indicating SNX10 regulates MMP9 secretion via the JNK-p38-ERK signaling pathway.","method":"Immunostaining; co-immunoprecipitation; siRNA knockdown; SNX10 overexpression; SNX10 knockout osteoclasts; western blotting for phospho-JNK/p38/ERK; MMP9 activity assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and co-localization plus KD/KO phenotype with pathway phosphorylation readout, single lab","pmids":["28498635"],"is_preprint":false},{"year":2017,"finding":"SNX10 splice-site mutation (c.212+1G>T) causes aberrant mRNA splicing with frameshift and premature stop, producing dysfunctional osteoclasts with defective ruffled borders that are unable to resorb bone despite forming sealing zones and appearing morphologically large and multinucleated.","method":"Whole exome sequencing; Sanger sequencing; SNX10 transcript analysis; functional analysis of patient-derived osteoclast progenitors; bone resorption assay in vitro","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived osteoclasts with functional phenotype analysis, transcript-level mechanistic confirmation, single study","pmids":["28592808"],"is_preprint":false},{"year":2017,"finding":"SNX10 promotes phagosome maturation in macrophages by recruiting the Mon1-Ccz1 complex to endosomes and phagosomes; SNX10 deficiency decreases bacterial killing ability of macrophages and increases susceptibility to Listeria monocytogenes infection in vivo.","method":"L. monocytogenes infection of macrophages; immunofluorescence co-localization; knockdown/knockout studies; in vivo infection of SNX10-deficient mice","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway placement via Mon1-Ccz1 recruitment with in vitro and in vivo phenotypic validation, single lab","pmids":["28903313"],"is_preprint":false},{"year":2018,"finding":"SNX10 controls chaperone-mediated autophagy (CMA) activity by mediating cathepsin A (CTSA) maturation; SNX10 directly interacts with CTSA (shown by pull-down assay); SNX10 deficiency inhibits CTSA maturation, increases LAMP-2A stability, and upregulates CMA activity, thereby activating Nrf2 and AMPK signaling pathways and protecting against alcohol-induced liver injury.","method":"Snx10 knockout mice; ethanol-fed Lieber-DeCarli model; pull-down assay (SNX10-CTSA interaction); western blotting for LAMP-2A; LAMP-2A siRNA interference; CMA activity assays; primary hepatocyte culture","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct pull-down interaction, KO mouse model with in vivo and in vitro corroboration, epistasis via LAMP-2A interference, multiple orthogonal methods","pmids":["29452206"],"is_preprint":false},{"year":2019,"finding":"SNX10 controls SRC protein levels by mediating autophagosome-lysosome fusion and SRC recruitment for autophagic degradation, thereby regulating SRC-STAT3 and SRC-CTNNB1 signaling pathways in colorectal epithelial cells.","method":"SNX10 KO mice and cell lines; autophagy flux assays (MAP1LC3, LAMP1, LAMP2); chloroquine treatment; co-localization of SRC with autophagic markers; western blotting for SRC, STAT3, CTNNB1 pathway components","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined molecular phenotype and pathway placement, multiple autophagy markers used, single lab","pmids":["31208298"],"is_preprint":false},{"year":2019,"finding":"SNX10 and PIKfyve co-localize to early endosomes in osteoclasts and co-immunoprecipitate in vesicle fractions; both are required for lysosome formation in osteoclasts; apilimod-specific inhibition of PIKfyve requires SNX10 expression and does not inhibit lysosome biogenesis in SNX10-deficient osteoclasts.","method":"Co-immunoprecipitation from vesicle fractions; confocal co-localization; overexpression studies; apilimod treatment; genetic deletion of PIKfyve; lysosome formation and TRAP secretion assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and co-localization with genetic epistasis (apilimod effect requires SNX10), single lab","pmids":["31692073"],"is_preprint":false},{"year":2019,"finding":"FKBP12 is a binding partner of SNX10 in osteoclasts; identified by yeast two-hybrid screening, validated by co-immunoprecipitation and co-localization; FKBP12, SNX10, and EEA1 are present in the same subcellular fractions (early endosomes) in osteoclasts.","method":"Yeast two-hybrid screening; co-immunoprecipitation; confocal co-localization; sucrose gradient subcellular fractionation","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus co-localization plus fractionation, single lab, no functional consequence directly demonstrated for the interaction","pmids":["30887568"],"is_preprint":false},{"year":2020,"finding":"The R51Q SNX10 knock-in mouse model displays massive osteopetrosis due to osteoclast inactivity caused by absence of ruffled borders and inability to secrete protons, confirming that the R51Q mutation is a causative factor in ARO.","method":"R51Q SNX10 knock-in mice; histological analysis of ruffled borders; extracellular proton secretion assay; bone density measurement","journal":"Bone","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic mouse model with multiple mechanistic readouts (ruffled border absence and proton secretion defect) replicating human disease mechanism","pmids":["32278070"],"is_preprint":false},{"year":2021,"finding":"The R51Q SNX10 mutation causes uncontrolled fusion of mature osteoclasts, generating giant dysfunctional osteoclasts; wild-type SNX10 provides a cell-autonomous mechanism that arrests fusion between mature osteoclasts. The R51Q SNX10 protein is unstable and exhibits altered lipid-binding properties, leading to reduced endocytotic activity and altered membrane homeostasis.","method":"R51Q SNX10 homozygous mice; time-lapse live imaging of osteoclast fusion; endocytosis assays; lipid-binding assays with R51Q mutant protein; cell size quantification","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse model plus multiple orthogonal assays (lipid binding, endocytosis, live fusion imaging) establishing cell-autonomous mechanism","pmids":["33975343"],"is_preprint":false},{"year":2021,"finding":"SNX10 recruits caspase-5 and PIKfyve to early endosomal membranes upon internalization of Gram-negative bacterial outer membrane vesicles (OMVs); this enables LPS release from OMVs into the cytosol, where caspase-5 activated by cytosolic LPS leads to Lyn phosphorylation, nuclear translocation of Snail/Slug, downregulation of E-cadherin, and intestinal barrier dysfunction.","method":"Co-immunoprecipitation; endosomal fractionation; SNX10 deletion in intestinal epithelial cells; caspase-5 activation assays; immunofluorescence; DC-SX029 SNX10 inhibitor treatment; colitis mouse model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, genetic KO, pharmacological inhibitor, in vivo model) establishing mechanistic pathway from SNX10 at endosome to downstream LPS sensing and signaling","pmids":["34747049"],"is_preprint":false},{"year":2022,"finding":"NSAIDs induce SNX10 upregulation via a CHOP-dependent ER stress response, which promotes CTSA maturation; matured CTSA then degrades LAMP2A, suppressing CMA activity, impairing PLIN2 degradation, and inducing hepatic lipid accumulation and hepatotoxicity.","method":"Mouse primary hepatocytes and HepG2 cells; diclofenac treatment; western blotting for LAMP2A/CTSA/SNX10; CMA reporter assay (KFERQ-PAmCherry); SNX10/LAMP2A overexpression; ER stress pathway analysis; in vivo diclofenac and AR7 administration","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple assays (reporter, protein levels, overexpression) in vitro and in vivo, replicating the SNX10-CTSA-LAMP2A axis from PMID:29452206, single lab","pmids":["35265214"],"is_preprint":false},{"year":2024,"finding":"SNX10 stabilizes LRP6 by direct interaction; gentisic acid binds SNX10 (confirmed by CETSA and DARTS assays), disrupts the SNX10-LRP6 interaction, and leads to LRP6 degradation, attenuating Wnt/β-catenin pathway activation and macrophage apoptosis in atherosclerotic plaques.","method":"CETSA assay; DARTS assay; co-immunoprecipitation of SNX10-LRP6; macrophage-specific SNX10 depletion in vivo; western blotting for LRP6 and β-catenin pathway components","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target engagement confirmed by CETSA/DARTS, protein interaction by co-IP, in vivo KO phenotype, single lab","pmids":["39603572"],"is_preprint":false},{"year":2024,"finding":"SNX10 regulates osteoclast fusion and size in vivo; SNX10-deficient mice display massive osteopetrosis with osteoclasts 2–6-fold larger (by volume and nuclear number) than wild-type, due to persistent DC-STAMP protein at the osteoclast periphery enabling uncontrolled fusion of mature osteoclasts.","method":"SNX10-knockout mice; EGFP-labeling of osteoclasts; 2-photon, confocal, and second harmonics generation microscopy; 3D volumetric analysis; DC-STAMP immunofluorescence","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with 3D imaging providing quantitative volumetric data, consistent with independent prior reports (PMID:33975343, PMID:32278070)","pmids":["39095084"],"is_preprint":false},{"year":2025,"finding":"SNX10 is a negative regulator of piecemeal mitophagy; in control conditions SNX10 localizes to early endosomes in a PtdIns3P-dependent manner; under hypoxia-mimicking conditions, SNX10-positive late endosomal structures acquire selected mitochondrial proteins (COX-IV, SAMM50) along with SQSTM1/p62 and LC3B. SNX10 depletion enhances COX-IV turnover, reduces mitochondrial respiration and citrate synthase activity; zebrafish lacking Snx10 show reduced Cox-IV levels, elevated ROS, and ROS-mediated neuronal death.","method":"SNX10 depletion in mammalian cells; mitochondrial respiration assay; citrate synthase activity assay; confocal imaging of endosome-mitochondria contacts; zebrafish snx10 knockout; ROS measurement; cell death assay in zebrafish brain","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (respiration, enzymatic activity, live imaging, in vivo zebrafish model) in a single study establishing SNX10 as modulator of piecemeal mitophagy","pmids":["40052924"],"is_preprint":false},{"year":2025,"finding":"SNX10 physically interacts with CLC-7 (lysosomal Cl-/H+ exchanger) and is required for trafficking of CLC-7- and OSTM1-containing lysosomes to the cell periphery in osteoclasts; all three proteins (SNX10, CLC-7, OSTM1) co-localize in LAMP1-positive lysosomes; SNX10-KO osteoclasts show few peripheral lysosomes containing CLC-7 and OSTM1.","method":"Co-immunoprecipitation of SNX10 and CLC-7; confocal co-localization of SNX10/CLC-7/OSTM1/LAMP1; comparative phenotyping of SNX10-KO, CLC-7-KO, and OSTM1-KO osteoclasts; osteoclast fusion kinetics analysis","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP of interaction plus co-localization plus genetic KO phenotype comparison across three proteins, establishing functional and physical link, single lab with preprint confirmation (bio_10.1101_2025.03.31.646258)","pmids":["41408708"],"is_preprint":false},{"year":2025,"finding":"SNX10 promotes HCoV-OC43 viral entry by facilitating phosphorylation of AP2M1 (AP2 complex subunit μ1), thereby enhancing clathrin-mediated viral endocytosis; SNX10 also promotes endosomal acidification to facilitate viral genome release; SNX10 knockout suppresses viral entry and triggers autophagy-mediated antiviral defense.","method":"IP-mass spectrometry identification of AP2M1 as SNX10 interactor; viral binding and internalization assays; SNX10 KO in vitro and in vivo; SNX10 reconstitution rescue; autophagy activation assays","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS interaction plus KO/rescue with functional viral entry assays, single lab","pmids":["40645503"],"is_preprint":false},{"year":2025,"finding":"SNX10 interacts with DEPDC5 and recruits it to lysosomes for CMA-mediated degradation; SNX10 knockdown accelerates DEPDC5 degradation, activating the mTORC1 pathway and elevating glycolysis in intestinal epithelial cells. α-hederin impairs the SNX10-DEPDC5 interaction, inhibiting this degradation pathway.","method":"Co-immunoprecipitation of SNX10-DEPDC5; lysosomal fractionation; CMA activity assays; SNX10 knockdown/rescue; mTORC1 activity (western blot); glycolysis enzyme assays; α-hederin treatment","journal":"Journal of pharmaceutical analysis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP interaction plus KD/rescue with lysosomal pathway and metabolic readouts, single lab","pmids":["41487148"],"is_preprint":false},{"year":2025,"finding":"Loss of SNX10 leads to elevated surface La protein on osteoclasts; inhibitory antibodies against La suppress excessive osteoclast hyperfusion in SNX10-mutant and OSTM1-mutant osteoclasts and restore resorptive function, linking SNX10-dependent membrane trafficking to regulation of surface La levels and osteoclast fusion control.","method":"Surface La detection by antibody staining; inhibitory anti-La antibody treatment of mutant osteoclasts; fusion assays; bone resorption assays; murine and human osteopetrosis cell models","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional antibody rescue experiment establishing causal link between SNX10 loss and elevated surface La, but preprint and single lab","pmids":["bio_10.1101_2025.09.07.674639"],"is_preprint":true}],"current_model":"SNX10 is a PX (extended phox-homology) domain-containing endosomal sorting protein that binds PtdIns3P and regulates multiple vesicular trafficking pathways: it targets V-ATPase to the centrosome for ciliogenesis and to the osteoclast ruffled border for bone resorption; it physically interacts with CLC-7 and controls lysosome trafficking to the osteoclast cell periphery, thereby regulating both osteoclast resorptive activity and cell-autonomous arrest of mature osteoclast fusion (with R51Q mutation causing instability, altered lipid binding, and uncontrolled hyperfusion via elevated surface La); it mediates CTSA maturation to control LAMP-2A stability and hence chaperone-mediated autophagy flux; it recruits autophagosome-lysosome fusion machinery for autophagic degradation of SRC; it promotes phagosome maturation via Mon1-Ccz1 recruitment; it acts as a negative regulator of piecemeal mitophagy through dynamic endosome-mitochondria contacts; and at the intestinal epithelium it recruits caspase-5 and PIKfyve to early endosomes to enable cytosolic LPS sensing from bacterial outer membrane vesicles."},"narrative":{"mechanistic_narrative":"SNX10 is a PtdIns3P-binding sorting nexin built around an extended phox-homology (PXe) domain that anchors it to endosomal membranes and governs multiple vesicular trafficking pathways across diverse cell types [PMID:25212774, PMID:40052924]. Through its association with the V-ATPase complex it targets acidification machinery to the centrosome, where it controls ciliary trafficking of Rab8a to enable ciliogenesis [PMID:21844891]. In osteoclasts SNX10 is essential for RANKL-induced differentiation, ruffled-border formation, extracellular acidification, and bone resorption [PMID:22174188, PMID:25811986], and it does so in part by physically interacting with the lysosomal Cl-/H+ exchanger CLC-7 to traffic CLC-7/OSTM1-containing lysosomes to the cell periphery [PMID:41408708]. SNX10 also imposes a cell-autonomous brake on the fusion of mature osteoclasts: its loss or the R51Q mutation produces giant dysfunctional osteoclasts via persistent peripheral DC-STAMP and elevated surface La protein, with R51Q SNX10 being unstable and exhibiting altered lipid binding and reduced endocytosis [PMID:32278070, PMID:33975343, PMID:39095084]. Causative SNX10 mutations — missense, splice-site, and the R51Q knock-in — produce autosomal recessive osteopetrosis with osteoclasts that form sealing zones but cannot resorb bone, and global loss additionally raises stomach pH and impairs calcium absorption to cause rickets [PMID:22499339, PMID:25811986, PMID:28592808, PMID:32278070]. Beyond bone, SNX10 organizes endolysosomal degradative routes: it directs cathepsin A (CTSA) maturation to control LAMP-2A stability and chaperone-mediated autophagy flux [PMID:29452206, PMID:35265214], mediates autophagic degradation of SRC [PMID:31208298], recruits the Mon1-Ccz1 complex to drive phagosome maturation and bacterial killing [PMID:28903313], and acts as a negative regulator of piecemeal mitophagy via dynamic endosome-mitochondria contacts that protect mitochondrial proteins from turnover [PMID:40052924]. At the intestinal epithelium SNX10 recruits caspase-5 and PIKfyve to early endosomes to enable cytosolic LPS sensing from bacterial outer membrane vesicles, triggering barrier dysfunction [PMID:34747049].","teleology":[{"year":2011,"claim":"Established SNX10 as a trafficking adaptor for the V-ATPase, linking it to a defined cellular structure (the centrosome) and process (ciliogenesis) rather than leaving it an orphan sorting nexin.","evidence":"Co-IP, centrosomal imaging, and loss-of-function with rescue in cultured cells and zebrafish","pmids":["21844891"],"confidence":"High","gaps":["Did not define the PtdIns3P/membrane basis of V-ATPase targeting","Relationship between ciliary and later osteoclast roles not addressed"]},{"year":2012,"claim":"Connected SNX10 to osteoclast biology and human osteopetrosis, showing it is required for differentiation and resorption and that a patient missense mutation perturbs the endosomal pathway.","evidence":"siRNA knockdown with resorption assays in osteoclasts; patient osteoclast and dextran endocytosis analysis with homozygosity mapping","pmids":["22174188","22499339"],"confidence":"Medium","gaps":["Molecular mechanism connecting SNX10 to ruffled border and acidification not yet defined","Reported nuclear/ER localization not reconciled with endosomal function"]},{"year":2014,"claim":"Solved the human SNX10 crystal structure, defining an extended PXe domain and pinpointing residues (Tyr32, Arg51) required for protein stability and vacuolation activity, providing a structural basis for disease mutations.","evidence":"X-ray crystallography at 2.6 A with structure-guided mutagenesis and vacuolation assays (building on the SNX11 PXe structure)","pmids":["25212774","23615901"],"confidence":"High","gaps":["Lipid-binding specificity not directly resolved in the structure","How the PXe helices engage partner proteins not shown"]},{"year":2015,"claim":"Used tissue-specific knockout mice to mechanistically separate SNX10's osteoclast resorption role from a distinct gastric epithelial role, explaining the combined osteopetrosis-plus-rickets phenotype.","evidence":"Global and osteoclast-specific Snx10 knockout mice with endocytosis, acidification, ruffled border, stomach pH assays and calcium rescue","pmids":["25811986"],"confidence":"High","gaps":["Direct trafficking substrate at the ruffled border not identified here","Gastric mechanism beyond pH/calcium absorption not detailed"]},{"year":2017,"claim":"Expanded SNX10 trafficking roles into MMP9 secretion in osteoclasts and Mon1-Ccz1-dependent phagosome maturation in macrophages, broadening its function from bone to innate immunity.","evidence":"Co-IP/co-localization and KD/KO with MMP9 activity and MAPK readouts; Listeria infection of SNX10-deficient macrophages and mice","pmids":["28498635","28903313"],"confidence":"Medium","gaps":["Whether MAPK changes are direct or downstream of trafficking defects unresolved","Mechanism of Mon1-Ccz1 recruitment by SNX10 not structurally defined"]},{"year":2017,"claim":"Confirmed via a splice-site mutation that loss of functional SNX10 yields morphologically large, multinucleated osteoclasts that form sealing zones but lack ruffled borders, foreshadowing a fusion-control role.","evidence":"Whole exome and transcript analysis with functional assays of patient-derived osteoclast progenitors","pmids":["28592808"],"confidence":"Medium","gaps":["Did not establish why mutant osteoclasts become large","No in vivo model in this study"]},{"year":2018,"claim":"Identified a direct SNX10-CTSA interaction controlling chaperone-mediated autophagy, defining a molecular substrate-maturation mechanism (CTSA maturation tuning LAMP-2A stability) for SNX10.","evidence":"Pull-down interaction, Snx10 KO mice in alcohol liver injury, LAMP-2A siRNA epistasis, CMA activity assays","pmids":["29452206"],"confidence":"High","gaps":["How SNX10 promotes CTSA maturation enzymatically not resolved","Generality of the CMA axis beyond liver not addressed here"]},{"year":2019,"claim":"Extended SNX10's degradative roles to autophagic clearance of SRC and to PIKfyve/FKBP12 partnerships at early endosomes required for osteoclast lysosome biogenesis.","evidence":"KO mice/cells with autophagy flux assays for SRC; co-IP, co-localization, Y2H, and apilimod epistasis for PIKfyve and FKBP12","pmids":["31208298","31692073","30887568"],"confidence":"Medium","gaps":["Functional consequence of the FKBP12 interaction not directly demonstrated","Whether SRC degradation and lysosome biogenesis roles share a common trafficking step unknown"]},{"year":2020,"claim":"A R51Q knock-in mouse demonstrated in vivo that this disease allele causes osteopetrosis through absent ruffled borders and failed proton secretion, validating the mutation as causative.","evidence":"R51Q knock-in mice with ruffled border histology, proton secretion, and bone density measurements","pmids":["32278070"],"confidence":"High","gaps":["Did not yet link the proton secretion defect to a specific trafficking cargo","Cellular instability of R51Q protein not quantified here"]},{"year":2021,"claim":"Defined a cell-autonomous fusion-arrest function: R51Q is unstable with altered lipid binding and reduced endocytosis, and wild-type SNX10 actively limits fusion of mature osteoclasts.","evidence":"R51Q homozygous mice with live fusion imaging, endocytosis assays, and lipid-binding assays on mutant protein","pmids":["33975343"],"confidence":"High","gaps":["Membrane effector linking lipid binding to fusion control not yet identified","Lipid species bound by wild-type vs R51Q not fully mapped"]},{"year":2021,"claim":"Placed SNX10 at the center of cytosolic LPS sensing, showing it recruits caspase-5 and PIKfyve to early endosomes to release LPS from bacterial OMVs and drive intestinal barrier dysfunction.","evidence":"Co-IP, endosomal fractionation, intestinal epithelial KO, caspase-5 activation assays, SNX10 inhibitor, and colitis mouse model","pmids":["34747049"],"confidence":"High","gaps":["How SNX10 selects OMV-containing endosomes not defined","Druggability of the SNX10-caspase-5 axis beyond initial inhibitor unexplored"]},{"year":2022,"claim":"Showed the SNX10-CTSA-LAMP2A axis is inducible by NSAID-driven CHOP-dependent ER stress, providing a regulatory input that suppresses CMA and causes hepatic lipid accumulation.","evidence":"Primary hepatocytes and HepG2 with diclofenac, CMA reporter, protein-level analyses, and in vivo NSAID/AR7 administration","pmids":["35265214"],"confidence":"Medium","gaps":["Direct CHOP regulation of the SNX10 locus not mapped","Reconciliation with opposite-direction CMA effects in other tissues incomplete"]},{"year":2024,"claim":"Resolved the molecular basis of osteoclast gigantism, showing SNX10 loss leaves DC-STAMP persistently at the periphery to permit uncontrolled fusion, with quantitative 3D volumetric confirmation.","evidence":"SNX10-KO mice with EGFP labeling, multiphoton/confocal/SHG imaging, 3D volume analysis, and DC-STAMP immunofluorescence","pmids":["39095084"],"confidence":"High","gaps":["Whether SNX10 directly traffics DC-STAMP not shown","Link between DC-STAMP and surface La regulation not addressed here"]},{"year":2024,"claim":"Broadened SNX10's adaptor function to Wnt signaling, showing it stabilizes LRP6 through direct interaction, with a small molecule (gentisic acid) disrupting this to attenuate Wnt/beta-catenin in atherosclerosis.","evidence":"CETSA/DARTS target engagement, SNX10-LRP6 co-IP, and macrophage-specific SNX10 depletion in vivo","pmids":["39603572"],"confidence":"Medium","gaps":["Membrane/endosomal step coupling SNX10 to LRP6 stability not defined","Generality beyond plaque macrophages unknown"]},{"year":2025,"claim":"Multiple studies converged on the trafficking effectors and substrates underlying SNX10's roles: CLC-7/OSTM1 lysosome positioning, surface La regulation, DEPDC5 turnover gating mTORC1, viral entry via AP2M1, and negative regulation of piecemeal mitophagy.","evidence":"Co-IP/co-localization/KO for CLC-7-OSTM1; antibody rescue for surface La (preprint); co-IP and CMA/mTORC1/glycolysis assays for DEPDC5; IP-MS and KO/rescue viral entry assays for AP2M1; respiration, citrate synthase, live imaging, and zebrafish KO for mitophagy","pmids":["41408708","bio_10.1101_2025.09.07.674639","41487148","40645503","40052924"],"confidence":"High","gaps":["Whether one PtdIns3P-anchored mechanism unifies these diverse cargoes is unresolved","Surface La result is a single-lab preprint awaiting peer review","Direct vs indirect handling of DEPDC5 and AP2M1 not fully distinguished"]},{"year":null,"claim":"It remains unknown how a single PtdIns3P-binding PXe domain protein achieves selectivity among its many cargoes and pathways (V-ATPase, CLC-7, CTSA, DC-STAMP, caspase-5, mitochondrial contacts), and what determines context-specific partner choice.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of SNX10 bound to any partner protein","No unifying biochemical principle for cargo selection across tissues","Lipid-binding determinants of wild-type SNX10 only partially mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4,14,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,8,15,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,17,22]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[11,12,15,19]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[9,20,22]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,8,11,20]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9,10,19,22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,5,13,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,15]}],"complexes":[],"partners":["CLC-7","OSTM1","CTSA","PIKFYVE","FKBP12","LRP6","DEPDC5","AP2M1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y5X0","full_name":"Sorting nexin-10","aliases":[],"length_aa":201,"mass_kda":23.6,"function":"Probable phosphoinositide-binding protein involved in protein sorting and membrane trafficking in endosomes. Plays a role in cilium biogenesis through regulation of the transport and the localization of proteins to the cilium. Required for the localization to the cilium of V-ATPase subunit ATP6V1D and ATP6V0D1, and RAB8A. Involved in osteoclast differentiation and therefore bone resorption","subcellular_location":"Cytoplasm; Endosome membrane; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q9Y5X0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX10","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SNX10","total_profiled":1310},"omim":[{"mim_id":"615085","title":"OSTEOPETROSIS, AUTOSOMAL RECESSIVE 8; OPTB8","url":"https://www.omim.org/entry/615085"},{"mim_id":"614780","title":"SORTING NEXIN 10; SNX10","url":"https://www.omim.org/entry/614780"},{"mim_id":"259700","title":"OSTEOPETROSIS, AUTOSOMAL RECESSIVE 1; OPTB1","url":"https://www.omim.org/entry/259700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Microtubules","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":43.2},{"tissue":"liver","ntpm":41.1}],"url":"https://www.proteinatlas.org/search/SNX10"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9Y5X0","domains":[{"cath_id":"3.30.1520.10","chopping":"10-152","consensus_level":"high","plddt":95.6395,"start":10,"end":152}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5X0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5X0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5X0-F1-predicted_aligned_error_v6.png","plddt_mean":85.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX10","jax_strain_url":"https://www.jax.org/strain/search?query=SNX10"},"sequence":{"accession":"Q9Y5X0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y5X0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y5X0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5X0"}},"corpus_meta":[{"pmid":"22499339","id":"PMC_22499339","title":"An 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SNX10 and V-ATPase together regulate ciliary trafficking of Rab8a, a critical regulator of ciliary membrane extension, establishing an SNX10/V-ATPase vesicular trafficking pathway required for ciliogenesis in vitro and in zebrafish in vivo.\",\n      \"method\": \"Loss-of-function assay in cultured cells and zebrafish morpholino knockdown; co-immunoprecipitation; confocal imaging of centrosomal targeting; rescue experiments\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction data, in vitro and in vivo (zebrafish) loss-of-function with specific phenotypic readout, pathway placement via epistasis with V-ATPase and Rab8a\",\n      \"pmids\": [\"21844891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SNX10 is required for RANKL-induced osteoclast formation and resorption activity; silencing SNX10 inhibits osteoclast differentiation, bone resorption on hydroxyapatite, and TRAP secretion. SNX10 localizes to the nucleus and endoplasmic reticulum in osteoclasts.\",\n      \"method\": \"siRNA knockdown of SNX10 in RANKL-stimulated osteoclast precursors; confocal immunofluorescence; subcellular fractionation; qPCR; hydroxyapatite resorption assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotypes using multiple orthogonal assays, single lab\",\n      \"pmids\": [\"22174188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A missense mutation in SNX10 in osteopetrosis patients results in an abnormally abundant mutant protein with altered distribution, fewer and smaller osteoclasts with markedly deranged resorptive capacity, and a perturbed endosomal pathway as evidenced by altered distribution of internalized dextran.\",\n      \"method\": \"Homozygosity mapping; analysis of patient osteoclasts; dextran endocytosis assay; immunostaining for SNX10 distribution\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional analysis of patient-derived osteoclasts with endosomal pathway readout, multiple patients studied\",\n      \"pmids\": [\"22499339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of SNX11 reveals a novel extended PX (PXe) domain with two additional C-terminal α-helices; these helices are indispensable for SNX11 in vitro function and the same PXe domain architecture is proposed to be present in SNX10, responsible for its vacuolation activity.\",\n      \"method\": \"X-ray crystallography of truncated SNX11; mutagenesis of C-terminal helices; vacuolation functional assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutagenesis validation, but direct structural work was on SNX11 with inference to SNX10\",\n      \"pmids\": [\"23615901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of human SNX10 at 2.6 Å resolution reveals an extended phox-homology (PXe) domain; Tyr32 and Arg51 are important for protein stability and vacuolation activity; disease-associated mutation Arg16Leu may affect SNX10 function through protein-protein interactions.\",\n      \"method\": \"X-ray crystallography; structure-guided mutagenesis; vacuolation activity assay\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutagenesis and functional vacuolation assay validating residue-level mechanism in a single rigorous study\",\n      \"pmids\": [\"25212774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Snx10-deficient osteoclasts show severely defective endocytosis, extracellular acidification, ruffled border formation, and bone resorption. Snx10 is also highly expressed in stomach epithelium and its loss leads to high stomach pH and impaired calcium absorption, causing rickets in addition to osteopetrosis.\",\n      \"method\": \"Global and osteoclast-specific Snx10 knockout mice; endocytosis assays; extracellular acidification measurement; histology of ruffled borders; bone resorption assays; stomach pH measurement; calcium supplementation rescue experiment\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with multiple orthogonal functional readouts and pharmacological rescue, clearly dissecting two tissue-specific mechanisms\",\n      \"pmids\": [\"25811986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SNX10 co-localizes with MMP9 and participates in MMP9 trafficking and secretion; SNX10 knockdown reduces MMP9 secretion and activity while increasing intracellular MMP9 protein; SNX10 knockout osteoclasts show downregulated phosphorylation of JNK, p38, and ERK, indicating SNX10 regulates MMP9 secretion via the JNK-p38-ERK signaling pathway.\",\n      \"method\": \"Immunostaining; co-immunoprecipitation; siRNA knockdown; SNX10 overexpression; SNX10 knockout osteoclasts; western blotting for phospho-JNK/p38/ERK; MMP9 activity assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and co-localization plus KD/KO phenotype with pathway phosphorylation readout, single lab\",\n      \"pmids\": [\"28498635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SNX10 splice-site mutation (c.212+1G>T) causes aberrant mRNA splicing with frameshift and premature stop, producing dysfunctional osteoclasts with defective ruffled borders that are unable to resorb bone despite forming sealing zones and appearing morphologically large and multinucleated.\",\n      \"method\": \"Whole exome sequencing; Sanger sequencing; SNX10 transcript analysis; functional analysis of patient-derived osteoclast progenitors; bone resorption assay in vitro\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived osteoclasts with functional phenotype analysis, transcript-level mechanistic confirmation, single study\",\n      \"pmids\": [\"28592808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SNX10 promotes phagosome maturation in macrophages by recruiting the Mon1-Ccz1 complex to endosomes and phagosomes; SNX10 deficiency decreases bacterial killing ability of macrophages and increases susceptibility to Listeria monocytogenes infection in vivo.\",\n      \"method\": \"L. monocytogenes infection of macrophages; immunofluorescence co-localization; knockdown/knockout studies; in vivo infection of SNX10-deficient mice\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway placement via Mon1-Ccz1 recruitment with in vitro and in vivo phenotypic validation, single lab\",\n      \"pmids\": [\"28903313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SNX10 controls chaperone-mediated autophagy (CMA) activity by mediating cathepsin A (CTSA) maturation; SNX10 directly interacts with CTSA (shown by pull-down assay); SNX10 deficiency inhibits CTSA maturation, increases LAMP-2A stability, and upregulates CMA activity, thereby activating Nrf2 and AMPK signaling pathways and protecting against alcohol-induced liver injury.\",\n      \"method\": \"Snx10 knockout mice; ethanol-fed Lieber-DeCarli model; pull-down assay (SNX10-CTSA interaction); western blotting for LAMP-2A; LAMP-2A siRNA interference; CMA activity assays; primary hepatocyte culture\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct pull-down interaction, KO mouse model with in vivo and in vitro corroboration, epistasis via LAMP-2A interference, multiple orthogonal methods\",\n      \"pmids\": [\"29452206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNX10 controls SRC protein levels by mediating autophagosome-lysosome fusion and SRC recruitment for autophagic degradation, thereby regulating SRC-STAT3 and SRC-CTNNB1 signaling pathways in colorectal epithelial cells.\",\n      \"method\": \"SNX10 KO mice and cell lines; autophagy flux assays (MAP1LC3, LAMP1, LAMP2); chloroquine treatment; co-localization of SRC with autophagic markers; western blotting for SRC, STAT3, CTNNB1 pathway components\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined molecular phenotype and pathway placement, multiple autophagy markers used, single lab\",\n      \"pmids\": [\"31208298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNX10 and PIKfyve co-localize to early endosomes in osteoclasts and co-immunoprecipitate in vesicle fractions; both are required for lysosome formation in osteoclasts; apilimod-specific inhibition of PIKfyve requires SNX10 expression and does not inhibit lysosome biogenesis in SNX10-deficient osteoclasts.\",\n      \"method\": \"Co-immunoprecipitation from vesicle fractions; confocal co-localization; overexpression studies; apilimod treatment; genetic deletion of PIKfyve; lysosome formation and TRAP secretion assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and co-localization with genetic epistasis (apilimod effect requires SNX10), single lab\",\n      \"pmids\": [\"31692073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FKBP12 is a binding partner of SNX10 in osteoclasts; identified by yeast two-hybrid screening, validated by co-immunoprecipitation and co-localization; FKBP12, SNX10, and EEA1 are present in the same subcellular fractions (early endosomes) in osteoclasts.\",\n      \"method\": \"Yeast two-hybrid screening; co-immunoprecipitation; confocal co-localization; sucrose gradient subcellular fractionation\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus co-localization plus fractionation, single lab, no functional consequence directly demonstrated for the interaction\",\n      \"pmids\": [\"30887568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The R51Q SNX10 knock-in mouse model displays massive osteopetrosis due to osteoclast inactivity caused by absence of ruffled borders and inability to secrete protons, confirming that the R51Q mutation is a causative factor in ARO.\",\n      \"method\": \"R51Q SNX10 knock-in mice; histological analysis of ruffled borders; extracellular proton secretion assay; bone density measurement\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic mouse model with multiple mechanistic readouts (ruffled border absence and proton secretion defect) replicating human disease mechanism\",\n      \"pmids\": [\"32278070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The R51Q SNX10 mutation causes uncontrolled fusion of mature osteoclasts, generating giant dysfunctional osteoclasts; wild-type SNX10 provides a cell-autonomous mechanism that arrests fusion between mature osteoclasts. The R51Q SNX10 protein is unstable and exhibits altered lipid-binding properties, leading to reduced endocytotic activity and altered membrane homeostasis.\",\n      \"method\": \"R51Q SNX10 homozygous mice; time-lapse live imaging of osteoclast fusion; endocytosis assays; lipid-binding assays with R51Q mutant protein; cell size quantification\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse model plus multiple orthogonal assays (lipid binding, endocytosis, live fusion imaging) establishing cell-autonomous mechanism\",\n      \"pmids\": [\"33975343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNX10 recruits caspase-5 and PIKfyve to early endosomal membranes upon internalization of Gram-negative bacterial outer membrane vesicles (OMVs); this enables LPS release from OMVs into the cytosol, where caspase-5 activated by cytosolic LPS leads to Lyn phosphorylation, nuclear translocation of Snail/Slug, downregulation of E-cadherin, and intestinal barrier dysfunction.\",\n      \"method\": \"Co-immunoprecipitation; endosomal fractionation; SNX10 deletion in intestinal epithelial cells; caspase-5 activation assays; immunofluorescence; DC-SX029 SNX10 inhibitor treatment; colitis mouse model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, genetic KO, pharmacological inhibitor, in vivo model) establishing mechanistic pathway from SNX10 at endosome to downstream LPS sensing and signaling\",\n      \"pmids\": [\"34747049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NSAIDs induce SNX10 upregulation via a CHOP-dependent ER stress response, which promotes CTSA maturation; matured CTSA then degrades LAMP2A, suppressing CMA activity, impairing PLIN2 degradation, and inducing hepatic lipid accumulation and hepatotoxicity.\",\n      \"method\": \"Mouse primary hepatocytes and HepG2 cells; diclofenac treatment; western blotting for LAMP2A/CTSA/SNX10; CMA reporter assay (KFERQ-PAmCherry); SNX10/LAMP2A overexpression; ER stress pathway analysis; in vivo diclofenac and AR7 administration\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple assays (reporter, protein levels, overexpression) in vitro and in vivo, replicating the SNX10-CTSA-LAMP2A axis from PMID:29452206, single lab\",\n      \"pmids\": [\"35265214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNX10 stabilizes LRP6 by direct interaction; gentisic acid binds SNX10 (confirmed by CETSA and DARTS assays), disrupts the SNX10-LRP6 interaction, and leads to LRP6 degradation, attenuating Wnt/β-catenin pathway activation and macrophage apoptosis in atherosclerotic plaques.\",\n      \"method\": \"CETSA assay; DARTS assay; co-immunoprecipitation of SNX10-LRP6; macrophage-specific SNX10 depletion in vivo; western blotting for LRP6 and β-catenin pathway components\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target engagement confirmed by CETSA/DARTS, protein interaction by co-IP, in vivo KO phenotype, single lab\",\n      \"pmids\": [\"39603572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNX10 regulates osteoclast fusion and size in vivo; SNX10-deficient mice display massive osteopetrosis with osteoclasts 2–6-fold larger (by volume and nuclear number) than wild-type, due to persistent DC-STAMP protein at the osteoclast periphery enabling uncontrolled fusion of mature osteoclasts.\",\n      \"method\": \"SNX10-knockout mice; EGFP-labeling of osteoclasts; 2-photon, confocal, and second harmonics generation microscopy; 3D volumetric analysis; DC-STAMP immunofluorescence\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with 3D imaging providing quantitative volumetric data, consistent with independent prior reports (PMID:33975343, PMID:32278070)\",\n      \"pmids\": [\"39095084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX10 is a negative regulator of piecemeal mitophagy; in control conditions SNX10 localizes to early endosomes in a PtdIns3P-dependent manner; under hypoxia-mimicking conditions, SNX10-positive late endosomal structures acquire selected mitochondrial proteins (COX-IV, SAMM50) along with SQSTM1/p62 and LC3B. SNX10 depletion enhances COX-IV turnover, reduces mitochondrial respiration and citrate synthase activity; zebrafish lacking Snx10 show reduced Cox-IV levels, elevated ROS, and ROS-mediated neuronal death.\",\n      \"method\": \"SNX10 depletion in mammalian cells; mitochondrial respiration assay; citrate synthase activity assay; confocal imaging of endosome-mitochondria contacts; zebrafish snx10 knockout; ROS measurement; cell death assay in zebrafish brain\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (respiration, enzymatic activity, live imaging, in vivo zebrafish model) in a single study establishing SNX10 as modulator of piecemeal mitophagy\",\n      \"pmids\": [\"40052924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX10 physically interacts with CLC-7 (lysosomal Cl-/H+ exchanger) and is required for trafficking of CLC-7- and OSTM1-containing lysosomes to the cell periphery in osteoclasts; all three proteins (SNX10, CLC-7, OSTM1) co-localize in LAMP1-positive lysosomes; SNX10-KO osteoclasts show few peripheral lysosomes containing CLC-7 and OSTM1.\",\n      \"method\": \"Co-immunoprecipitation of SNX10 and CLC-7; confocal co-localization of SNX10/CLC-7/OSTM1/LAMP1; comparative phenotyping of SNX10-KO, CLC-7-KO, and OSTM1-KO osteoclasts; osteoclast fusion kinetics analysis\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP of interaction plus co-localization plus genetic KO phenotype comparison across three proteins, establishing functional and physical link, single lab with preprint confirmation (bio_10.1101_2025.03.31.646258)\",\n      \"pmids\": [\"41408708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX10 promotes HCoV-OC43 viral entry by facilitating phosphorylation of AP2M1 (AP2 complex subunit μ1), thereby enhancing clathrin-mediated viral endocytosis; SNX10 also promotes endosomal acidification to facilitate viral genome release; SNX10 knockout suppresses viral entry and triggers autophagy-mediated antiviral defense.\",\n      \"method\": \"IP-mass spectrometry identification of AP2M1 as SNX10 interactor; viral binding and internalization assays; SNX10 KO in vitro and in vivo; SNX10 reconstitution rescue; autophagy activation assays\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS interaction plus KO/rescue with functional viral entry assays, single lab\",\n      \"pmids\": [\"40645503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX10 interacts with DEPDC5 and recruits it to lysosomes for CMA-mediated degradation; SNX10 knockdown accelerates DEPDC5 degradation, activating the mTORC1 pathway and elevating glycolysis in intestinal epithelial cells. α-hederin impairs the SNX10-DEPDC5 interaction, inhibiting this degradation pathway.\",\n      \"method\": \"Co-immunoprecipitation of SNX10-DEPDC5; lysosomal fractionation; CMA activity assays; SNX10 knockdown/rescue; mTORC1 activity (western blot); glycolysis enzyme assays; α-hederin treatment\",\n      \"journal\": \"Journal of pharmaceutical analysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP interaction plus KD/rescue with lysosomal pathway and metabolic readouts, single lab\",\n      \"pmids\": [\"41487148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of SNX10 leads to elevated surface La protein on osteoclasts; inhibitory antibodies against La suppress excessive osteoclast hyperfusion in SNX10-mutant and OSTM1-mutant osteoclasts and restore resorptive function, linking SNX10-dependent membrane trafficking to regulation of surface La levels and osteoclast fusion control.\",\n      \"method\": \"Surface La detection by antibody staining; inhibitory anti-La antibody treatment of mutant osteoclasts; fusion assays; bone resorption assays; murine and human osteopetrosis cell models\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional antibody rescue experiment establishing causal link between SNX10 loss and elevated surface La, but preprint and single lab\",\n      \"pmids\": [\"bio_10.1101_2025.09.07.674639\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SNX10 is a PX (extended phox-homology) domain-containing endosomal sorting protein that binds PtdIns3P and regulates multiple vesicular trafficking pathways: it targets V-ATPase to the centrosome for ciliogenesis and to the osteoclast ruffled border for bone resorption; it physically interacts with CLC-7 and controls lysosome trafficking to the osteoclast cell periphery, thereby regulating both osteoclast resorptive activity and cell-autonomous arrest of mature osteoclast fusion (with R51Q mutation causing instability, altered lipid binding, and uncontrolled hyperfusion via elevated surface La); it mediates CTSA maturation to control LAMP-2A stability and hence chaperone-mediated autophagy flux; it recruits autophagosome-lysosome fusion machinery for autophagic degradation of SRC; it promotes phagosome maturation via Mon1-Ccz1 recruitment; it acts as a negative regulator of piecemeal mitophagy through dynamic endosome-mitochondria contacts; and at the intestinal epithelium it recruits caspase-5 and PIKfyve to early endosomes to enable cytosolic LPS sensing from bacterial outer membrane vesicles.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNX10 is a PtdIns3P-binding sorting nexin built around an extended phox-homology (PXe) domain that anchors it to endosomal membranes and governs multiple vesicular trafficking pathways across diverse cell types [#4, #19]. Through its association with the V-ATPase complex it targets acidification machinery to the centrosome, where it controls ciliary trafficking of Rab8a to enable ciliogenesis [#0]. In osteoclasts SNX10 is essential for RANKL-induced differentiation, ruffled-border formation, extracellular acidification, and bone resorption [#1, #5], and it does so in part by physically interacting with the lysosomal Cl-/H+ exchanger CLC-7 to traffic CLC-7/OSTM1-containing lysosomes to the cell periphery [#20]. SNX10 also imposes a cell-autonomous brake on the fusion of mature osteoclasts: its loss or the R51Q mutation produces giant dysfunctional osteoclasts via persistent peripheral DC-STAMP and elevated surface La protein, with R51Q SNX10 being unstable and exhibiting altered lipid binding and reduced endocytosis [#13, #14, #18]. Causative SNX10 mutations — missense, splice-site, and the R51Q knock-in — produce autosomal recessive osteopetrosis with osteoclasts that form sealing zones but cannot resorb bone, and global loss additionally raises stomach pH and impairs calcium absorption to cause rickets [#2, #5, #7, #13]. Beyond bone, SNX10 organizes endolysosomal degradative routes: it directs cathepsin A (CTSA) maturation to control LAMP-2A stability and chaperone-mediated autophagy flux [#9, #16], mediates autophagic degradation of SRC [#10], recruits the Mon1-Ccz1 complex to drive phagosome maturation and bacterial killing [#8], and acts as a negative regulator of piecemeal mitophagy via dynamic endosome-mitochondria contacts that protect mitochondrial proteins from turnover [#19]. At the intestinal epithelium SNX10 recruits caspase-5 and PIKfyve to early endosomes to enable cytosolic LPS sensing from bacterial outer membrane vesicles, triggering barrier dysfunction [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established SNX10 as a trafficking adaptor for the V-ATPase, linking it to a defined cellular structure (the centrosome) and process (ciliogenesis) rather than leaving it an orphan sorting nexin.\",\n      \"evidence\": \"Co-IP, centrosomal imaging, and loss-of-function with rescue in cultured cells and zebrafish\",\n      \"pmids\": [\"21844891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the PtdIns3P/membrane basis of V-ATPase targeting\", \"Relationship between ciliary and later osteoclast roles not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected SNX10 to osteoclast biology and human osteopetrosis, showing it is required for differentiation and resorption and that a patient missense mutation perturbs the endosomal pathway.\",\n      \"evidence\": \"siRNA knockdown with resorption assays in osteoclasts; patient osteoclast and dextran endocytosis analysis with homozygosity mapping\",\n      \"pmids\": [\"22174188\", \"22499339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism connecting SNX10 to ruffled border and acidification not yet defined\", \"Reported nuclear/ER localization not reconciled with endosomal function\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Solved the human SNX10 crystal structure, defining an extended PXe domain and pinpointing residues (Tyr32, Arg51) required for protein stability and vacuolation activity, providing a structural basis for disease mutations.\",\n      \"evidence\": \"X-ray crystallography at 2.6 A with structure-guided mutagenesis and vacuolation assays (building on the SNX11 PXe structure)\",\n      \"pmids\": [\"25212774\", \"23615901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid-binding specificity not directly resolved in the structure\", \"How the PXe helices engage partner proteins not shown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Used tissue-specific knockout mice to mechanistically separate SNX10's osteoclast resorption role from a distinct gastric epithelial role, explaining the combined osteopetrosis-plus-rickets phenotype.\",\n      \"evidence\": \"Global and osteoclast-specific Snx10 knockout mice with endocytosis, acidification, ruffled border, stomach pH assays and calcium rescue\",\n      \"pmids\": [\"25811986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct trafficking substrate at the ruffled border not identified here\", \"Gastric mechanism beyond pH/calcium absorption not detailed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Expanded SNX10 trafficking roles into MMP9 secretion in osteoclasts and Mon1-Ccz1-dependent phagosome maturation in macrophages, broadening its function from bone to innate immunity.\",\n      \"evidence\": \"Co-IP/co-localization and KD/KO with MMP9 activity and MAPK readouts; Listeria infection of SNX10-deficient macrophages and mice\",\n      \"pmids\": [\"28498635\", \"28903313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MAPK changes are direct or downstream of trafficking defects unresolved\", \"Mechanism of Mon1-Ccz1 recruitment by SNX10 not structurally defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed via a splice-site mutation that loss of functional SNX10 yields morphologically large, multinucleated osteoclasts that form sealing zones but lack ruffled borders, foreshadowing a fusion-control role.\",\n      \"evidence\": \"Whole exome and transcript analysis with functional assays of patient-derived osteoclast progenitors\",\n      \"pmids\": [\"28592808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish why mutant osteoclasts become large\", \"No in vivo model in this study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a direct SNX10-CTSA interaction controlling chaperone-mediated autophagy, defining a molecular substrate-maturation mechanism (CTSA maturation tuning LAMP-2A stability) for SNX10.\",\n      \"evidence\": \"Pull-down interaction, Snx10 KO mice in alcohol liver injury, LAMP-2A siRNA epistasis, CMA activity assays\",\n      \"pmids\": [\"29452206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SNX10 promotes CTSA maturation enzymatically not resolved\", \"Generality of the CMA axis beyond liver not addressed here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended SNX10's degradative roles to autophagic clearance of SRC and to PIKfyve/FKBP12 partnerships at early endosomes required for osteoclast lysosome biogenesis.\",\n      \"evidence\": \"KO mice/cells with autophagy flux assays for SRC; co-IP, co-localization, Y2H, and apilimod epistasis for PIKfyve and FKBP12\",\n      \"pmids\": [\"31208298\", \"31692073\", \"30887568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the FKBP12 interaction not directly demonstrated\", \"Whether SRC degradation and lysosome biogenesis roles share a common trafficking step unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A R51Q knock-in mouse demonstrated in vivo that this disease allele causes osteopetrosis through absent ruffled borders and failed proton secretion, validating the mutation as causative.\",\n      \"evidence\": \"R51Q knock-in mice with ruffled border histology, proton secretion, and bone density measurements\",\n      \"pmids\": [\"32278070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet link the proton secretion defect to a specific trafficking cargo\", \"Cellular instability of R51Q protein not quantified here\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a cell-autonomous fusion-arrest function: R51Q is unstable with altered lipid binding and reduced endocytosis, and wild-type SNX10 actively limits fusion of mature osteoclasts.\",\n      \"evidence\": \"R51Q homozygous mice with live fusion imaging, endocytosis assays, and lipid-binding assays on mutant protein\",\n      \"pmids\": [\"33975343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Membrane effector linking lipid binding to fusion control not yet identified\", \"Lipid species bound by wild-type vs R51Q not fully mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed SNX10 at the center of cytosolic LPS sensing, showing it recruits caspase-5 and PIKfyve to early endosomes to release LPS from bacterial OMVs and drive intestinal barrier dysfunction.\",\n      \"evidence\": \"Co-IP, endosomal fractionation, intestinal epithelial KO, caspase-5 activation assays, SNX10 inhibitor, and colitis mouse model\",\n      \"pmids\": [\"34747049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SNX10 selects OMV-containing endosomes not defined\", \"Druggability of the SNX10-caspase-5 axis beyond initial inhibitor unexplored\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed the SNX10-CTSA-LAMP2A axis is inducible by NSAID-driven CHOP-dependent ER stress, providing a regulatory input that suppresses CMA and causes hepatic lipid accumulation.\",\n      \"evidence\": \"Primary hepatocytes and HepG2 with diclofenac, CMA reporter, protein-level analyses, and in vivo NSAID/AR7 administration\",\n      \"pmids\": [\"35265214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CHOP regulation of the SNX10 locus not mapped\", \"Reconciliation with opposite-direction CMA effects in other tissues incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the molecular basis of osteoclast gigantism, showing SNX10 loss leaves DC-STAMP persistently at the periphery to permit uncontrolled fusion, with quantitative 3D volumetric confirmation.\",\n      \"evidence\": \"SNX10-KO mice with EGFP labeling, multiphoton/confocal/SHG imaging, 3D volume analysis, and DC-STAMP immunofluorescence\",\n      \"pmids\": [\"39095084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SNX10 directly traffics DC-STAMP not shown\", \"Link between DC-STAMP and surface La regulation not addressed here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Broadened SNX10's adaptor function to Wnt signaling, showing it stabilizes LRP6 through direct interaction, with a small molecule (gentisic acid) disrupting this to attenuate Wnt/beta-catenin in atherosclerosis.\",\n      \"evidence\": \"CETSA/DARTS target engagement, SNX10-LRP6 co-IP, and macrophage-specific SNX10 depletion in vivo\",\n      \"pmids\": [\"39603572\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Membrane/endosomal step coupling SNX10 to LRP6 stability not defined\", \"Generality beyond plaque macrophages unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple studies converged on the trafficking effectors and substrates underlying SNX10's roles: CLC-7/OSTM1 lysosome positioning, surface La regulation, DEPDC5 turnover gating mTORC1, viral entry via AP2M1, and negative regulation of piecemeal mitophagy.\",\n      \"evidence\": \"Co-IP/co-localization/KO for CLC-7-OSTM1; antibody rescue for surface La (preprint); co-IP and CMA/mTORC1/glycolysis assays for DEPDC5; IP-MS and KO/rescue viral entry assays for AP2M1; respiration, citrate synthase, live imaging, and zebrafish KO for mitophagy\",\n      \"pmids\": [\"41408708\", \"bio_10.1101_2025.09.07.674639\", \"41487148\", \"40645503\", \"40052924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether one PtdIns3P-anchored mechanism unifies these diverse cargoes is unresolved\", \"Surface La result is a single-lab preprint awaiting peer review\", \"Direct vs indirect handling of DEPDC5 and AP2M1 not fully distinguished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how a single PtdIns3P-binding PXe domain protein achieves selectivity among its many cargoes and pathways (V-ATPase, CLC-7, CTSA, DC-STAMP, caspase-5, mitochondrial contacts), and what determines context-specific partner choice.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of SNX10 bound to any partner protein\", \"No unifying biochemical principle for cargo selection across tissues\", \"Lipid-binding determinants of wild-type SNX10 only partially mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 14, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 8, 15, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 17, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [11, 12, 15, 19]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [9, 20, 22]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 8, 11, 20]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9, 10, 19, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 5, 13, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CLC-7\", \"OSTM1\", \"CTSA\", \"PIKfyve\", \"FKBP12\", \"LRP6\", \"DEPDC5\", \"AP2M1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}